title: Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1.
abstract: Programmed death 1 (PD-1) signaling through its ligands, PD-L1 and PD-L2, has been known to negatively regulate T-cell responses. In addition, PD-L1 has been shown to interact with B7-1 costimulatory molecule to inhibit T-cell responses. Extensive studies have shown that PD-1/PD-L blockade restores exhausted T cells during chronic viral infections and tumors. In this study, we evaluated the effects of soluble PD-1 (sPD-1) as a blockade of PD-1 and PD-L1 on vaccine-elicited antigen-specific T-cell responses in mice. Coadministration of sPD-1 DNA with human papilloma virus-16 E7 DNA vaccine significantly enhanced E7-specific CD8(+) T-cell responses, resulting in potent antitumor effects against E7-expressing tumors. We also found that sPD-1, codelivered with adenovirus-based vaccine, could increase antigen-specific CD8(+) T-cell responses, indicating vaccine type-independent adjuvant effect of sPD-1. In addition, the frequency and functional activity of adoptively transferred OT-I cells, particularly memory CD8(+) T cells, were augmented by coadministration of sPD-1 DNA, which was closely associated with increased T-cell proliferation and reduced T-cell apoptosis through upregulation of Bcl-xL expression during T-cell activation. Codelivery of sPD-1 DNA also enhanced maturation of dendritic cells (DCs) in vivo which was accompanied by upregulation of DC maturation markers such as major histocompatibility complex class II. Taken together, our findings show that sPD-1 potently enhances codelivered antigen-specific CD8(+) T-cell responses and in vivo maturation of DCs during activation of naive CD8(+) T cells, suggesting that an immunization strategy with sPD-1 as an adjuvant can be used to increase antigen-specific T-cell immunity elicited by vaccination.
authors.affiliation: Division of Molecular and Life Science, Integrative Bioscience and Biotechnology, WCU, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Nam
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Choi
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010212:Papilloma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D050725:Papillomavirus E7 Proteins / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; C105992:PDCD1 protein, human; D050725:Papillomavirus E7 Proteins; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA